PROJECT SUMMARY Current therapies for patients with advanced or metastatic pheochromocytoma/paraganglioma (PGL/PCC) are not curative and there are no known molecular or genetic markers to predict penetrance of primary or metastatic disease. Although most patients have sporadic tumors, up to 40% have a hereditary cause for their PGL/PCC, with at least 12 different susceptibility genes identified. The Succinate Dehydrogenase Subunit (SDH) genes form complex II of the mitochondrial respiratory chain and are involved with the Kreb?s cycle converting succinate to fumarate. Germline pathogenic variants in any of the SDHx genes increases risk of developing Hereditary PGL/PCC Syndrome. This syndrome is defined by the development of multifocal primary PGL/PCC, renal cell carcinoma and gastrointestinal stromal tumors. The penetrance for the disease in carriers of SDHx pathogenic germline variants varies per gene. Furthermore, there are no predictive markers for primary tumor development or metastatic disease. This gap in understanding between genotype and phenotype makes clinical recommendations for screening and surveillance difficult and creates an unmet need in the field. The goals of this proposal are to identify genetic risk loci for developing PGL/PCC to better understand the etiology of the cancer and to identify genetic modifiers for SDHx-associated PGL/PCC to be directly translatable to clinical care for prediction of cancer risk and prognosis as well as identification of therapeutic targets for cancer prevention and treatment. Leveraging the international American-Australian-Asian Adrenal Alliance (A5) consortium, we have assembled the largest known sample set of 1740 germline DNAs and matched clinical data from patients with sporadic and SDHx-associated PGL/PCC as well as patients with germline SDHx pathogenic variants without PGL/PCC. In Aim 1, we will determine the inherited genetic risk loci for PGL/PCC to better understand the genetic etiology of the cancer by performing a case control genome-wide SNP analysis. In Aim 2, we will determine inherited genetic risk modifiers for SDHx pathogenic variant carriers to develop PGL/PCC by performing a case-control study between SDHx carriers with and without disease. Aim 3 focuses on rare variants within the SDH complex which may be modifiers for SDHB-associated PGL/PCC. SDHB carriers are at highest risk for developing metastatic disease. Finally, using several methods including eQTL analysis and regulatory element analysis, we will identify the most likely causal variants to test with in vitro functional assays. Successful identification of genetic modifiers for sporadic or SDHx-associated PGL/PCC will have direct translation to clinical care by identifying those at highest risk for a personalized screening approach and identifying targets for cancer prevention and therapeutic intervention.